Crystalline forms of valacyclovir hydrochloride

ABSTRACT

In this invention the novel polymorphs of the valacyclovir hydrochloride and methods for preparing these novel polymorphs are provided.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a National Stage entry of International ApplicationNo. PCT/TR2003/000048 filed May 30, 2003, the entire specificationclaims and drawings of which are incorporated herewith by reference.

BACKGROUND OF THE INVENTION

Valacyclovir is an amino acid derivative of the acyclovir which is anacyclic analog of natural nucleoside guanine. Acyclovir shows selectiveand strong antiviral activity, especially against herpes simplexviruses.

Acyclovir lacks 3′-hydroxyl group at the side chain and so terminateschain elongation step of the viral DNA during DNA replication. See,Goodman et al, in The Pharmacological Basis of Therapeutics 1193-1198(9^(th) ed. 1996). The chemical name of the acyclovir is2-Amino-1,9-dihydro-9-[(2-hydroxyethoxy)methyl]-6H-purin-6-one] and theCAS Registry number is 59277-89-3. Formula I shows the chemicalstructure of acyclovir.

The chemical name of the valacyclovir hydrochloride is L-Valine2-[(2-amino-1,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl esterhydrochloride and the CAS Registry number is 124832-26-4. Formula IIshows the chemical structure of valacyclovir hydrochloride.

Although acyclovir shows strong antiviral activity (Schaeffer et al,Nature 1978, 272, 583), it is poorly absorbed from the gastrointestinaltrack. Because of this low bioavailability of acyclovir, multiple highdoses of the oral drug must be taken.

However α-amino group of the valacyclovir can form hydrochloride saltand this increases the solubility and bioavailability of the drugwithout loosing its antiviral activity (see, for example U.S. Pat. No.4,957,924 ).

Valacyclovir hydrochloride is prepared following the basic patent EP0308 065. Preparation of an anhydrous form of valacyclovir hydrochlorideis described in U.S. Pat. No. 6,107,302. In another patent application(WO 03/022209 A2) more polymorphs of the antiviral valacyclovirhydrochloride are reported.

Discovery of the new crystalline forms of the active pharmaceuticalsprovides new possibilities for the formulation studies and can increasethe stability of the active ingredients.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows a representative x-ray diffraction pattern of valacyclovirhydrochloride in form VIII.

FIG. 2 shows a representative x-ray diffraction pattern of valacyclovirhydrochloride in form IX.

FIG. 3 shows a representative x-ray diffraction pattern of valacyclovirhydrochloride in form X.

FIG. 4 shows a representative x-ray diffraction pattern of valacyclovirhydrochloride in form XI.

FIG. 5 shows a representative x-ray diffraction pattern of valacyclovirhydrochloride in form XII.

FIG. 6 shows a representative x-ray diffraction pattern of valacyclovirhydrochloride in form XIII.

FIG. 7 shows a representative x-ray diffraction pattern of valacyclovirhydrochloride in form XIV.

SUMMARY OF THE INVENTION

It is an aspect of the present invention to provide novel polymorphsVIII, IX, X, XI, XII, XIII, and XIV of valacyclovir hydrochloride and aswell as admixtures of two or more of these forms.

It is another aspect of the invention to provide procedures for thepreparation of the crystalline forms VIII, IX, X, XI, XII, XIII, andXIV.

It is one aspect, the present invention relates to valacyclovirhydrochloride in form VIII characterized by x-ray diffraction peaks(reflections) at about 3.5, 6.6, 9.2, 14.3, 15.6, 16.2, 16.5, 16.9,19.0, 19.9, 21.3, 22.8, 24.0, 26.7, 27.2, and 27.8±2 degrees two theta.

In another aspect, the present invention also relates to valacyclovirhydrochloride in form VIII having x-ray powder diffraction pattern asshown in FIG. 1.

It is also an aspect, the present invention relates to valacyclovirhydrochloride in form VIII having the water content between about 0.1%to 10%, particularly between about 0.5% to 3% determined by Karl Fischeranalysis.

It is one aspect, the present invention relates to valacyclovirhydrochloride in form IX characterized by x-ray diffraction peaks(reflections) at about 3.6, 7.0, 8.5, 9.4, 10.6, 10.8, 13.2, 15.4, 16.4,20.1, 20.8, 21.3, 23.8, 24.6, 25.9, 26.3, 26.7, 27.2 and 27.8±2 degreestwo theta.

In another aspect, the present invention also relates to valacyclovirhydrochloride in form IX having x-ray powder diffraction pattern asshown in FIG. 2.

It is also an aspect, the present invention relates to valacyclovirhydrochloride in form IX having the water content between about 0.1% to10%, particularly between about 6% to 10% determined by Karl Fischeranalysis.

It is one aspect, the present invention relates to valacyclovirhydrochloride in form X characterized by x-ray diffraction peaks(reflections) at about 6.9, 9.4, 11.6, 14.7, 15.9, 16.7, 17.2, 19.2,21.5, 23.1, 24.2, 26.5, 27.5, and 28.0±2 degrees two theta. In anotheraspect, the present invention also relates to valacyclovir hydrochloridein form X having x-ray powder diffraction pattern as shown in FIG. 3.

It is also an aspect, the present invention relates to valacyclovirhydrochloride in form X having the water content between about 0.1% to10%, particularly between about 3% to 7% determined by Karl Fischeranalysis.

It is one aspect, the present invention relates to valacyclovirhydrochloride in form XI characterized by x-ray diffraction peaks(reflections) at about 6.7, 9.3, 11.1, 12.2, 14.6, 15.9, 16.7, 20.1,21.6, 23.0, 24.1, 26.1, 27.3, 30.6, and 32.0±2 degrees two theta.

In another aspect, the present invention also relates to valacyclovirhydrochloride in form XI having x-ray powder diffraction pattern asshown in FIG. 4.

It is also an aspect, the present invention relates to valacyclovirhydrochloride in form XI having the water content between about 0.1% to10%, particularly between about 1% to 3% determined by Karl Fischeranalysis.

It is one aspect, the present invention relates to valacyclovirhydrochloride in form XII characterized by x-ray diffraction peaks(reflections) at about 6.9, 9.5, 11.6, 15.6, 15.8, 17.2, 19.3, 21.6,23.1, 26.6, 27.6, and 28.1±2 degrees two theta.

In another aspect, the present invention also relates to valacyclovirhydrochloride in form XII having x-ray powder diffraction pattern asshown in FIG. 5.

It is also an aspect, the present invention relates to valacyclovirhydrochloride in form XII having the water content between about 0.1% to10%, particularly between about 0.5% to 9% determined by Karl Fischeranalysis.

It is one aspect, the present invention relates to valacyclovirhydrochloride in form XIII characterized by x-ray diffraction peaks(reflections) at about 3.6, 6.6, 9.2, 15.4, 15.6, 16.9, 19.0, 21.3,22.8, 26.3, 27.2, and 27.8±2 degrees two theta.

In another aspect, the present invention also relates to valacyclovirhydrochloride in form XIII having x-ray powder diffraction pattern asshown in FIG. 6.

It is also an aspect, the present invention relates to valacyclovirhydrochloride in form XIII having the water content between about 0.1%to 10%, particularly between about 3% to 5% determined by Karl Fischeranalysis.

It is one aspect, the present invention relates to valacyclovirhydrochloride in form XIV characterized by x-ray diffraction peaks(reflections) at about 3.3, 3.6, 6.7, 9.3, 9.5, 10.6, 10.9, 13.3, 15.3,15.7, 16.4, 20.1, 21.4, 24.0, 26.3, 26.9, 27.2, and 27.9±2 degrees twotheta.

In another aspect, the present invention also relates to valacyclovirhydrochloride in form XIV having x-ray powder diffraction pattern asshown in FIG. 7.

It is also an aspect, the present invention relates to valacyclovirhydrochloride in form XIV having the water content between about 0.1% to10%, particularly between about 6% to 9% determined by Karl Fischeranalysis.

In another aspect, the present invention relates to a process forpreparing valacyclovir hydrochloride form VIII, including the step ofdissolving valacyclovir hydrochloride in dimethylformamide (DMF) andprecipitating by adding ethyl acetate then isolating valacyclovirhydrochloride in form VIII from this mixture.

It is another aspect, carrying the experiment at a temperature betweenabout −10 to 18° C., particularly between about 0 to 5° C. and dryingthe valacyclovir hydrochloride form VIII at a temperature between about20 to 80° C.

In another aspect, the present invention relates to a process forpreparing valacyclovir hydrochloride form IX, including the step ofdissolving valacyclovir hydrochloride in methanol and precipitating byadding n-hexanes then isolating valacyclovir hydrochloride in form IXfrom this mixture.

It is another aspect, carrying the experiment at a temperature betweenabout −10 to 18° C., particularly between about 0 to 5° C. and dryingthe valacyclovir hydrochloride form IX at a temperature between about 20to 80° C.

In another aspect, the present invention relates to a process forpreparing valacyclovir hydrochloride form X, including the step ofdissolving valacyclovir hydrochloride in dimethylformamide (DMF) andprecipitating by adding acetone then isolating valacyclovirhydrochloride in form X from this mixture.

It is another aspect, carrying the experiment at a temperature betweenabout 20 to 60° C., particularly between about 20 to 30° C. and dryingthe valacyclovir hydrochloride form X at a temperature between about 20to 80° C. particularly about 45 to 55° C.

In another aspect, the present invention relates to a process forpreparing valacyclovir hydrochloride form XI, including the step ofdissolving valacyclovir hydrochloride in dimethylformamide (DMF) andprecipitating by adding ethyl acetate then isolating valacyclovirhydrochloride in form XI from this mixture.

It is another aspect, carrying the experiment at a temperature betweenabout 20 to 60° C., particularly between about 20 to 30° C. and dryingthe valacyclovir hydrochloride form XI at a temperature between about 20to 80° C. particularly about 45 to 55° C.

In another aspect, the present invention relates to a process forpreparing valacyclovir hydrochloride form XII, including the step ofdissolving valacyclovir hydrochloride in dimethylformamide (DMF) or inmethanol and precipitating by adding acetone, diethylether or n-hexanesthen isolating valacyclovir hydrochloride in form XII from this mixture.

It is another aspect, carrying the experiment at a temperature betweenabout 20 to 70° C., particularly between about 20 to 65° C. and dryingthe valacyclovir hydrochloride form XII at a temperature between about20 to 80° C. particularly about 45 to 55° C.

In another aspect, the present invention relates to a process forpreparing valacyclovir hydrochloride form XIII, including the step ofdissolving valacyclovir hydrochloride in dimethylformamide (DMF) andprecipitating by adding acetone then isolating valacyclovirhydrochloride in form XIII from this mixture.

It is another aspect, carrying the experiment at a temperature betweenabout −10 to 25° C., particularly between about 0 to 5° C. and dryingthe valacyclovir hydrochloride form XIII at a temperature between about20 to 80° C. particularly about 45 to 55° C.

In another aspect, the present invention relates to a process forpreparing valacyclovir hydrochloride form XIV, including the step ofdissolving valacyclovir hydrochloride in methanol and precipitating byadding acetone then isolating valacyclovir hydrochloride in form XIVfrom this mixture.

It is another aspect, carrying the experiment at a temperature betweenabout 20 to 60° C., particularly between about 20 to 30° C. and dryingthe valacyclovir hydrochloride form XIV at a temperature between about20 to 80° C. particularly about 45 to 55° C.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel polymorphs VII, IX, X, XI, XII,XIII, and XIV of valacyclovir hydrochloride and as well as admixtures oftwo or more of these forms.

The invention also provides procedures for the preparation of thecrystalline forms VHI, IX, X, XI, XII, XIII, and XIV as well asadmixtures of two or more of these forms.

A Schmadzu RDX 6000 x-ray diffractometer is used for the measurements ofx-ray diffractograms. The scanning range was 2-70 degrees two-theta. Thesamples were grounded before analysis.

The water content of the crystalline forms (polymorphs andpseudo-polymorphs) is measured by using Karl Fischer instrumentfollowing method given in the 1990 US Pharmacopoeia at pages 1619-1621and in European Pharmacopoeia (1992, part 2, sixteen fascicule at v.3.5. 6-1).

According to HPLC analysis, initially used valacyclovir hydrochloridewhich produced following EP 308 065 has a purity of more than 99.5%(based on area %).

The present invention provides a method for producing valacyclovirhydrochloride in form VIII which comprises the step of dissolvingvalacyclovir hydrochloride in DMF with stirring for 10-60 minutes at atemperature between about 20-25° C. and cooling to 0-5° C., thenprecipitating by adding acetone and stirring for another 10-60 minutesat this temperature. The solid so formed is isolated by filtration. Thematerial is dried under reduced pressure at a temperature between about20° C. to about 80° C., preferably at 50° C. for 15 hours. The productobtained following this procedure is valacyclovir hydrochloride in formVIII according to x-ray diffraction analysis.

The present invention provides a method for producing valacyclovirhydrochloride in form IX which comprises the step of dissolvingvalacyclovir hydrochloride in methanol with stirring for 10-60 minutesat a temperature between about 20-80° C., preferably at 65° C. andcooling to 0-5° C., then precipitating by adding n-hexanes and stirringfor another 10-60 minutes at this temperature. The solid so formed isisolated by filtration. The material is dried under reduced pressure ata temperature between about 20° C. to about 80° C., preferably at 50° C.for 15 hours. The product obtained following this procedure isvalacyclovir hydrochloride in form IX according to x-ray diffractionanalysis.

The present invention provides a method for producing valacyclovirhydrochloride in form X which comprises the step of dissolvingvalacyclovir hydrochloride in DMF with stirring for 10-60 minutes at atemperature between about 20-25° C., then precipitating by addingacetone and stirring for another 10-60 minutes at this temperature. Thesolid so formed is isolated by filtration. The material is dried underreduced pressure at a temperature between about 20° C. to about 80° C.,preferably at 50° C. for 15 hours. The product obtained following thisprocedure is valacyclovir hydrochloride in form X according to x-raydiffraction analysis.

The present invention provides a method for producing valacyclovirhydrochloride in form XI which comprises the step of dissolvingvalacyclovir hydrochloride in DMF with stirring for 10-60 minutes at atemperature between about 20-25° C., then precipitating by adding ethylacetate and stirring for another 10-60 minutes at this temperature. Thesolid so formed is isolated by filtration. The material is dried underreduced pressure at a temperature between about 20° C. to about 80° C.,preferably at 50° C. for 15 hours. The product obtained following thisprocedure is valacyclovir hydrochloride in form XM according to x-raydiffraction analysis.

The present invention provides a method for producing valacyclovirhydrochloride in form XII which comprises the step of dissolvingvalacyclovir hydrochloride in DMF with stirring for 10-60 minutes at atemperature between about 20-25° C., then precipitating by addingacetone, diethylether or n-hexanes and stirring for another 10-60minutes at this temperature. The solid so formed is isolated byfiltration. The material is dried under reduced pressure at atemperature between about 20° C. to about 80° C., preferably at 50° C.for 15 hours. The product obtained following this procedure isvalacyclovir hydrochloride in form XII according to x-ray diffractionanalysis.

The present invention provides a method for producing valacyclovirhydrochloride in form XIII which comprises the step of dissolvingvalacyclovir hydrochloride in DMF with stirring for 10-60 minutes at atemperature between about 20-25° C. and cooling to 0-5° C., thenprecipitating by adding acetone and stirring for another 10-60 minutesat this temperature. The solid so formed is isolated by filtration. Thematerial is dried under reduced pressure at a temperature between about20° C. to about 80° C., preferably at 50° C. for 15 hours. The productobtained following this procedure is valacyclovir hydrochloride in formXIII according to x-ray diffraction analysis.

The present invention provides a method for producing valacyclovirhydrochloride in form XMV which comprises the step of dissolvingvalacyclovir hydrochloride in methanol with stirring for 10-60 minutesat a temperature between about 40-80° C., preferably at 65° C. thenprecipitating by adding n-hexanes and stirring for another 10-60 minuteswhile cooling to ambient temperature. The solid so formed is isolated byfiltration. The material is dried under reduced pressure at atemperature between about 20° C. to about 80° C., preferably at 50° C.for 15 hours. The product obtained following this procedure isvalacyclovir hydrochloride in form XIV according to x-ray diffractionanalysis.

EXAMPLES Preparation of Crystalline Forms of Valacyclovir HydrochlorideExample 1

Valacyclovir hydrochloride (1.0 g) was dissolved in DMF (5.0 mL) withstirring for 15-20 minutes at room temperature and cooled to 0° C. Thenit was precipitated with ethyl acetate (20.0 mL). After stirring another15-20 minutes at this temperature, the crystals were filtered and driedat 50° C. for 15 hours to give valacyclovir hydrochloride form VIR.

-   Water content (K.F.): 1.4502%.

Example 2

Valacyclovir hydrochloride (1.0 g) was dissolved in methanol (8.0 mL)with stirring for 15-20 minutes at reflux temperature and cooled to 0°C. Then it was precipitated with n-hexanes (20.0 mL) at thistemperature. After stirring 15-20 minutes at 0° C., the crystals werefiltered and dried at 50° C. for 15 hours to give valacyclovirhydrochloride form IX.

-   Water content (K.F.): 6.6874%.

Example 3

Valacyclovir hydrochloride (1.0 g) was dissolved in DMF (5.0 mL) withstirring for 15-20 minutes at room temperature and precipitated withacetone (20.0 mL) at 22-24° C. After stirring 15-20 minutes at thistemperature, the crystals were filtered and dried at 50° C. for 15 hoursto give valacyclovir hydrochloride form X.

-   Water content (K.F.): 5.8720%.

Example 4

Valacyclovir hydrochloride (1.0 g) was dissolved in DMF (5.0 mL) withstirring for 15-20 minutes at room temperature and precipitated withethyl acetate (20.0 mL) at 22-24° C. After stirring 15-20 minutes atthis temperature the crystals were filtered and dried at 50° C. for 15hours to give valacyclovir hydrochloride form XI.

-   Water content (K.F.): 1.8328%.

Example 5

Valacyclovir hydrochloride (1.0 g) was dissolved in DMF (5.0 mL) withstirring for 15-20 minutes at room temperature and precipitated withdiethylether (20.0 mL) at 22-24° C. After stirring 15-20 minutes at thistemperature the crystals were filtered and dried at 50° C. for 15 hoursto give valacyclovir hydrochloride form XII.

-   Water content (K.F.): 0.8583%.

Example 6

Valacyclovir hydrochloride (1.0 g) was dissolved in DMF (5.0 mL) withstirring for 15-20 minutes at room temperature and precipitated withn-hexanes (20.0 mL) at 22-24° C. After stirring 15-20 minutes at thistemperature the crystals were filtered and dried at 50° C. for 15 hoursto give valacyclovir hydrochloride form XII.

-   Water content (K.F.): 0.6872%.

Example 7

Valacyclovir hydrochloride (1.0 g) was dissolved in methanol (8.0 mL)with stirring for 15-20 minutes at reflux temperature and precipitatedimmediately by the addition of acetone (20.0 mL). After stirring 15-20minutes at ambient temperature, the crystals were filtered and dried at50° C. for 15 hours to give valacyclovir hydrochloride form XII.

-   Water content (K.F.): 6.7046%.

Example 8

Valacyclovir hydrochloride (1.0 g) was dissolved in methanol (8.0 mL)with stirring for 15-20 minutes at reflux temperature, cooled to roomtemperature and precipitated by the addition of diethylether (20.0 mL).After stirring 15-20 minutes at ambient temperature, the crystals werefiltered and dried at 50° C. for 15 hours to give valacyclovirhydrochloride form XII.

-   Water content (K.F.): 7.7137%.

Example 9

Valacyclovir hydrochloride (1.0 g) was dissolved in DMF (5.0 mL) withstirring for 15-20 minutes at room temperature and cooled to 0° C. Thenit was precipitated with acetone (20.0 mL). After stirring 15-20 minutesat this temperature, the crystals were filtered and dried at 50° C. for15 hours to give valacyclovir hydrochloride form XIII.

-   Water content (K.F.): 4.4783%.

Example 10

Valacyclovir hydrochloride (1.0 g) was dissolved in methanol (8.0 mL)with stirring for 15-20 minutes at reflux temperature and precipitatedimmediately by the addition of n-hexanes (20.0 mL). After stirring 15-20minutes at ambient temperature, the crystals were filtered and dried at50° C. for 15 hours to give valacyclovir hydrochloride form XIV.

-   Water content (K.F.): 6.5580%.

1. A method of producing valacyclovir hydrochloride in crystal formVIII, comprising the steps of: dissolving valacyclovir hydrochloride indimethylformamide at a temperature ranging from about 20 to 25° C.,cooling the solution to a temperature ranging from about 0 to 5° C. andprecipitating valacyclovir hydrochloride by adding ethyl acetate,isolating valacyclovir hydrochloride from the mixture in form VIII, andoptionally drying isolated valacyclovir hydrochloride.
 2. A method forproducing valacyclovir hydrochloride in crystal form IX, comprising thesteps of: dissolving valacyclovir hydrochloride in methanol at atemperature ranging from about 20 to 80° C., cooling the solution to atemperature ranging from about 0 to 5° C. and precipitating valacyclovirhydrochloride by adding n-hexanes, isolating valacyclovir hydrochloridefrom the mixture in form IX, and optionally drying the isolatedvalacyclovir hydrochloride.
 3. A method for producing valacyclovirhydrochloride crystals according to claim 2, wherein the dissolving stepis conducted at a temperature of about 65° C.
 4. A method for producingvalacyclovir hydrochloride in crystal form X, comprising the steps of:dissolving valacyclovir hydrochloride in dimethylformamide at atemperature ranging from about 20 to 25° C., precipitating the same byadding acetone, isolating valacyclovir hydrochloride from the mixture inform X, and optionally drying the isolated valacyclovir hydrochloride.5. A method for producing valacyclovir hydrochloride in crystal form XI,comprising the steps of: dissolving valacyclovir hydrochloride indimethylformamide at a temperature ranging from about 20 to 25° C.,precipitating the same by adding ethyl acetate, isolating valacyclovirhydrochloride from the mixture in form XI, and optionally drying theisolated valacyclovir hydrochloride.
 6. A method for producingvalacyclovir hydrochloride in crystal form XII, comprising the steps of:dissolving valacyclovir hydrochloride in dimethylformamide at atemperature ranging from about 20 to 25° C., precipitating the same byadding a reagent selected from the group consisting of n-hexanes anddiethylether, isolating valacyclovir hydrochloride from the mixture inform XII, and optionally drying the isolated valacyclovir hydrochloride.7. A method for producing valacyclovir hydrochloride in crystal formXIII, comprising the steps of: dissolving valacyclovir hydrochloride indimethylformamide at a temperature ranging from about 20 to 25° C.,cooling the solution to a temperature ranging from about 0 to 5° C. andprecipitating the same by adding acetone, isolating valacyclovirhydrochloride from the mixture in form XIII, and optionally drying theisolated valacyclovir hydrochloride.
 8. A method for producingvalacyclovir hydrochloride in crystal form XIV, comprising the steps of:dissolving valacyclovir hydrochloride in methanol at a temperatureranging from about 40 to 80° C., cooling the solution to about ambienttemperature and precipitating the same by adding n-hexanes, isolatingvalacyclovir hydrochloride from the mixture in form XIV, and optionallydrying the isolated valacyclovir hydrochloride.
 9. A method forproducing valacyclovir hydrochloride crystals according to claim 8,wherein the dissolving step is conducted at a temperature about 65° C.10. A method according to claim 1, wherein the isolated sample is driedat a reduced pressure and at a temperature ranging from 20° C. to 80° C.for a duration of 1 to 24 hours to yield crystals having water contentof about 0.5% to 3% according to Karl Fischer analysis method.
 11. Amethod for producing valacyclovir hydrochloride in crystal form XII,comprising the steps of: dissolving valacyclovir hydrochloride inmethanol at about reflux temperature, precipitating the same by adding areagent selected from the group consisting of acetone and diethylether,isolating valacyclovir hydrochloride from the mixture in form XII, andoptionally drying the isolated valacyclovir hydrochloride.
 12. A methodaccording to claim 2 wherein the isolated sample is dried at a reducedpressure, and at a temperature ranging from 20° C. to 80° C. for aduration of 1 to 24 hours to yield crystals having water content ofabout 6% to 10% according to Karl Fischer analysis method.
 13. A methodaccording to claim 4 wherein the isolated sample is dried at a reducedpressure, and at a temperature ranging from 20° C. to 80° C. for aduration of 1 to 24 hours to yield crystals having water content ofabout 3% to 7% according to Karl Fischer analysis method.
 14. A methodaccording to claim 5 wherein the isolated sample is dried at a reducedpressure, and at a temperature ranging from 20° C. to 80° C. for aduration of 1 to 24 hours to yield crystals having water content ofabout 1% to 3% according to Karl Fischer analysis method.
 15. A methodaccording to claim 2 wherein the isolated sample is dried at a reducedpressure, and at a temperature ranging from 20° C. to 80° C. for aduration of 1 to 24 hours to yield crystals having water content ofabout 0.5% to 9% according to Karl Fischer analysis method.
 16. A methodaccording to claim 11 wherein the isolated sample is dried at a reducedpressure, and at a temperature ranging from 20° C. to 80° C. for aduration of 1 to 24 hours to yield crystals having water content ofabout 0.5% to 9% according to Karl Fischer analysis method.
 17. A methodaccording to claim 7 wherein the isolated sample is dried at a reducedpressure, and at a temperature ranging from 20° C. to 80° C. for aduration of 1 to 24 hours to yield crystals having water content ofabout 3% to 5% according to Karl Fischer analysis method.
 18. A methodaccording to claim 8 wherein the isolated sample is dried at a reducedpressure, and at a temperature ranging from 20° C. to 80° C. for aduration of 1 to 24 hours to yield crystals having water content ofabout 6% to 9% according to Karl Fischer analysis method.